Nicotine addiction is both deadly and costly: tobacco use is the most common form of preventable death in the United States and a conservative estimate of the cost to society is upwards of $150 billion. Nicotine, along with all drugs of addiction, is known to alter dopamine function. It has been established that dopamine encodes errors in reward prediction that guide learning and behavior. How the dopamine system responds to counterfactual information, or information about "what could have been," remains an open question. A recent human neuroimaging study found neural signals in the striatum consistent with computation of a "fictive error" in normal and nicotine-addicted subjects (cigarette smokers), but unlike normal subjects, this computation had no influence on smokers'behavior. Though the striatum is innervated by dopamine neurons, because the signal measured with functional magnetic resonance imaging (fMRI) is thought to reflect synaptic current, these striatal responses cannot be conclusively linked to dopamine. The goals of this proposal are threefold: (i) we will use non-invasive fMRI methods tailored the brainstem environment, where dopamine neurons are located, to investigate whether and how the dopamine system encodes counterfactual information, (ii) we will investigate whether working memory load is a possible mechanism by which counterfactual information computations do not influence nicotine addicts'behavior, and (iii) we aim to identify if increasing the saliency of counterfactual information enables nicotine addicts to incorporate counterfactual information into their decision-making behavior. The experiments outlined in this proposal constitute the first brainstem fMRI of the dopamine system in nicotine-addicted subjects and open the door for more detailed and also translational studies of brainstem responses to other drugs of addiction. ) PUBLIC HEALTH RELEVANCE: Approximately one-fourth of Americans smoke cigarettes despite being aware of the dire health risks associated with tobacco use. The experiments in this proposal test how the brain processes and uses counterfactual information, or information about "what could have been." Determining how the addicted brain processes counterfactual information is an important step towards understanding and treating nicotine addiction.